title: Improvement of the efficacy of 5-aminolevulinic acid-mediated photodynamic treatment in human oral squamous cell carcinoma HSC-4.
abstract: Ever since protoporphyrin IX (PpIX) was discovered to accumulate preferentially in cancer cells after 5-aminolevulinic acid (ALA) treatment, photodynamic treatment or therapy (PDT) has been developed as an exciting new treatment option for cancer patients. However, the level of PpIX accumulation in oral cancer is fairly low and insufficient for PDT. Ferrochelatase (FECH) and ATP-binding cassette transporter G2 (ABCG2) are known to regulate PpIX accumulation. In addition, serum enhances PpIX export by ABCG2. We investigated here whether and how inhibitors of FECH and ABCG2 and their combination could improve PpIX accumulation and PDT efficacy in an oral cancer cell line in serum-containing medium. ABCG2 inhibitor and the combination of ABCG2 and FECH inhibitors increased PpIX in the presence of fetal bovine serum (FBS) in an oral cancer cell line. Analysis of ABCG2 gene silencing also revealed the involvement of ABCG2 in the regulation of PpIX accumulation. Inhibitors of FECH and ABCG2, and their combination increased the efficiency of ALA-PDT even in the presence of FBS. ALA-PDT-induced cell death was accompanied by apoptotic events and lipid peroxidation. These results suggest that accumulation of PpIX is determined by the activities of ABCG2 and FECH and that treatment with a combination of their inhibitors improves the efficacy of PDT for oral cancer, especially in the presence of serum.
authors.affiliation: Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. gmd421001@s.okayama-u.ac.jp
authors.forename: Masanao
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Naoki
authors.initials: N
authors.lastname: Katase
authors.forename: Keiji
authors.initials: K
authors.lastname: Inoue
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagatsuka
authors.forename: Kozo
authors.initials: K
authors.lastname: Utsumi
authors.forename: Junzo
authors.initials: J
authors.lastname: Sasaki
authors.forename: Hideyo
authors.initials: H
authors.lastname: Ohuchi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D005294:Ferrochelatase / Q000037:antagonists & inhibitors; D020868:Gene Silencing; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011524:Protoporphyrins / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000590:Amino Acid Chloromethyl Ketones; D001798:Blood Proteins; D061945:Caspase Inhibitors; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D017262:Siderophores; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D005294:Ferrochelatase; D003676:Deferoxamine